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Although modern radiation therapy delivers a localized distribution of ionizing energy that can be used to cure primary cancers for many patients, the inevitable radiation exposure to non-targeted normal tissue leads to a risk of a radiation-related new cancer. Modern therapies often produce a complex spectrum of secondary particles, both charged and uncharged, that must be considered both in their physical radiation transport throughout the patient and their potential to induce biological damage, which depends on the microscopic energy deposition from the cascade of primary, secondary, and downstream particles. This work summarizes the experimental data for relative biological effectiveness for particles associated with modern radiotherapy in light of their capacity to induce secondary malignancies in patients. A distinction is highlighted between the radiobiological experimental data and the coarser metrics used frequently in radiation protection. For critical assessment of the risks of secondary malignancies for patients undergoing radiation therapy, a detailed description of primary and secondary radiation fields is needed, though not routinely considered for individual patient treatments. Furthermore, not only the particle type, but also the microscopic dose and track structure, must be considered, which points to a demand for detailed physics models and high-performance computing strategies to model the risks.
PURPOSE - This work proposes a theoretical framework that enables comparative risk predictions for second cancer incidence after particle beam therapy for different ion species for individual patients, accounting for differences in relative biological effectiveness (RBE) for the competing processes of tumor initiation and cell inactivation. Our working hypothesis was that use of carbon-ion therapy instead of proton therapy would show a difference in the predicted risk of second cancer incidence in the breast for a sample of Hodgkin lymphoma (HL) patients.
METHODS AND MATERIALS - We generated biologic treatment plans and calculated relative predicted risks of second cancer in the breast by using two proposed methods: a full model derived from the linear quadratic model and a simpler linear-no-threshold model.
RESULTS - For our reference calculation, we found the predicted risk of breast cancer incidence for carbon-ion plans-to-proton plan ratio,
, to be 0.75 ± 0.07 but not significantly smaller than 1 (P=.180).
CONCLUSIONS - Our findings suggest that second cancer risks are, on average, comparable between proton therapy and carbon-ion therapy.
Copyright © 2016 Elsevier Inc. All rights reserved.
BACKGROUND - The incidence of secondary malignancies is increased in patients with malignant and premalignant conditions. Although neuroendocrine tumors (NET) are uncommon, their incidence is increasing. We evaluated the rate of additional malignancies in patients with NET.
METHODS - Using the Surveillance, Epidemiology, and End Results (SEER) database, we identified a cohort of patients with pancreatic NET (PNET) or gastrointestinal NET (GINET). We determined the incidence of additional cancers diagnosed either before or after the diagnosis of PNET or GINET, by comparing these rates with the general population. Using multivariable regression, we evaluated factors that increased the risk of an additional malignancy.
RESULTS - A cohort of 9,727 NET patients was identified. A total of 3,086 additional cancers occurred in 2,508 patients (25.8 %). The most common sites of additional malignancies included colorectal (21.1 %), prostate (14.5 %), breast (13.3 %), and lung (11.6 %). Among patients with PNET, the incidence of breast, lung, uterine, lymph, and pancreatic cancers was less than expected in the general population, whereas in patients with GINET, the observed incidence of nearly all malignancies exceeded that expected. Increasing age, marital status, and localized NET were associated with increased risk.
CONCLUSION - Our study shows that the incidence of additional malignancies in patients with PNET and GINET is 25.8 %. Patients with GINET are at increased risk of additional malignancies, whereas patients with PNET have a decreased risk compared with the general population. More vigilant surveillance for secondary malignancies should be performed in patients with GINET. Studies investigating potential etiologic oncogenic pathways are warranted.
Type II topoisomerases are essential enzymes that modulate DNA under- and overwinding, knotting, and tangling. Beyond their critical physiological functions, these enzymes are the targets for some of the most widely prescribed anticancer drugs (topoisomerase II poisons) in clinical use. Topoisomerase II poisons kill cells by increasing levels of covalent enzyme-cleaved DNA complexes that are normal reaction intermediates. Drugs such as etoposide, doxorubicin, and mitoxantrone are frontline therapies for a variety of solid tumors and hematological malignancies. Unfortunately, their use also is associated with the development of specific leukemias. Regimens that include etoposide or doxorubicin are linked to the occurrence of acute myeloid leukemias that feature rearrangements at chromosomal band 11q23. Similar rearrangements are seen in infant leukemias and are associated with gestational diets that are high in naturally occurring topoisomerase II-active compounds. Finally, regimens that include mitoxantrone and epirubicin are linked to acute promyelocytic leukemias that feature t(15;17) rearrangements. The first part of this article will focus on type II topoisomerases and describe the mechanism of enzyme and drug action. The second part will discuss how topoisomerase II poisons trigger chromosomal breaks that lead to leukemia and potential approaches for dissociating the actions of drugs from their leukemogenic potential.
© 2014 New York Academy of Sciences.
PURPOSE - The diagnosis of childhood leukemia now carries a much improved overall survival. With this knowledge comes concern for late effects of therapy, especially the risk of secondary malignancy.
METHODS - Patients diagnosed with AML or ALL between the ages of 0 and 18 years who survived at least 5 years after diagnosis were included in analysis. Cumulative incidence of subsequent malignancy at 30 years was calculated. To compare incidence of subsequent malignancies with rates of the US population, standardized incidence ratios (SIRs) were calculated.
RESULTS - Four thousand eight hundred six patients were included in the analysis. Median follow-up was 14.5 years (range 5.0-35.9 years). A total of 82 patients developed a second malignancy. The most common second tumor was brain (24 %) followed by thyroid (22 %). Cumulative incidences of secondary malignancy at 30 years for ALL patients and AML patients were 3.9 and 4.3 %, respectively (p = 0.10). Patients were at an increased risk of malignancy compared to the US population (SIR = 3.9, 95 % CI = 3.2-4.8). The SIR for all malignancies for patients diagnosed between 1973 and 1979, 1980 and 1989, and 1990 and 1999 were 2.1 (95 % CI = 1.3-3.4), 4.3 (95 % CI = 3.1-5.9), and 4.4 (95 % CI = 2.7-6.6), respectively.
CONCLUSIONS - Although incidence of secondary malignancy at 30 years in survivors of childhood leukemia is low, the rate exceeds the expected rate of malignancy for a cohort of this age by nearly 4:1. The development of a subsequent malignancy has significant impact on overall-survival and continued research is needed to assess the long-term risk of subsequent malignancy with modern therapy.
IMPLICATIONS FOR CANCER SURVIVORS - Although survivors of childhood leukemia experience an increased rate of malignancy compared to their peers, the development of a subsequent malignancy is still a rare event. However, continued long-term follow-up is warranted.
Merkel cell carcinoma is an aggressive neoplasm of the skin that shows frequent lymph node metastases, but has only rarely been reported in the bone marrow. Herein we report a case of a 64-year-old male with a history of plasma cell myeloma and recent skin diagnosis of Merkel cell carcinoma who presented for a routine follow-up bone marrow to assess his myeloma. The biopsy showed persistent plasma cell myeloma, trilineage dysplasia, and clusters of neuroendocrine cells consistent with metastatic Merkel cell carcinoma. Discussion of this case, a review of metastatic Merkel cell carcinoma, and identification of clinical settings in which staging bone marrow biopsy may be warranted are presented.
Childhood autologous hematopoietic cell transplant (auto-HCT) survivors can be at risk for secondary malignant neoplasms (SMNs). We assembled a cohort of 1487 pediatric auto-HCT recipients to investigate the incidence and risk factors for SMNs. Primary diagnoses included neuroblastoma (39%), lymphoma (26%), sarcoma (18%), central nervous system tumors (14%) and Wilms tumor (2%). Median follow-up was 8 years (range, <1-21 years). SMNs were reported in 35 patients (AML/myelodysplastic syndrome (MDS)=13, solid cancers=20, subtype missing=2). The overall cumulative incidence of SMNs at 10 years from auto-HCT was 2.60% (AML/MDS=1.06%, solid tumors=1.30%). We found no association between SMNs risk and age, gender, diagnosis, disease status, time since diagnosis or use of TBI or etoposide as part of conditioning. OS at 5-years from diagnosis of SMNs was 33% (95% confidence interval (CI), 16-52%). When compared with age- and gender-matched general population, auto-HCT recipients had 24 times higher risks of developing SMNs (95% CI, 16.0-33.0). Notable SMN sites included bone (N=5 SMNs, observed (O)/expected (E)=81), thyroid (N=5, O/E=53), breast (N=2, O/E=93), soft tissue (N=2, O/E=34), AML (N=6, O/E=266) and MDS (N=7, O/E=6603). Risks of SMNs increased with longer follow-up from auto-HCT. Pediatric auto-HCT recipients are at considerably increased risk for SMNs and need life-long surveillance for SMNs.
BACKGROUND - Vitamin D levels and calcium intake have been associated with risk of colorectal neoplasia, and genetic variation in vitamin D pathway genes may affect circulating vitamin D metabolite concentrations and/or risk for colorectal lesions. This study evaluated associations between polymorphic variation in the Gc-globulin (GC) and calcium-sensing receptor (CASR) and odds for metachronous colorectal neoplasia and vitamin D metabolite concentrations.
METHODS - Participants from the Ursodeoxycholic Acid (UDCA) and Wheat Bran Fiber (WBF) trials (n = 1,439) were analyzed using a single-nucleotide polymorphism (SNP) tagging approach, with a subset (n = 404) of UDCA trial participants for whom vitamin D metabolite concentrations were also available. A total of 25 GC and 35 CASR tagSNPs were evaluated using multiple statistical methods.
RESULTS - Principal components analyses did not reveal gene-level associations between GC or CASR and colorectal neoplasia; however, a significant gene-level association between GC and 25(OH)D concentrations (P < 0.01) was observed. At the individual SNP level and following multiple comparisons adjustments, significant associations were observed between seven GC (rs7041, rs222035, rs842999, rs1155563, rs12512631, rs16846876, and rs1746825) polymorphisms and circulating measures of 25(OH)D (adjusted P < 0.01) and CASR SNP rs1042636 and proximal colorectal neoplasia (adjusted P = 0.01).
CONCLUSIONS - These results show a possible association between variation in CASR and odds of colorectal neoplasia as well as the potential role of variation in GC with circulating 25(OH)D concentrations.
IMPACT - Additional research is warranted to determine the mechanism of GC genotype in influencing 25(OH)D concentrations and to further elucidate the role of CASR in colorectal neoplasia.
Survivors of childhood cancer have a higher risk of developing a secondary neoplasm in their lifetime. The increased risk of a second malignant neoplasm is related to treatment of the primary tumor and genetic predisposition. We describe a 19-year-old man with 2 hepatic masses, one of which was diagnosed as a hepatic angiomyolipoma and the other as focal nodular hyperplasia 14 years after the treatment of stage IV pelvic rhabdomyosarcoma. The combination of these tumors has not previously been reported in the literature.
Copyright © 2011 Elsevier Inc. All rights reserved.